1. Field of the Invention
This invention provides substituted 1,2-substituted 5-pyrrolidinone compounds, methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including preterm labor, ovulation induction, cervical ripening, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, including erectile dysfunction, osteoporosis and other destructive bone disease or disorder, renal dysfunction (acute and chronic), immune deficiency disorder or disease, dry eye, skin disorders such as ichthyosis, elevated intra-ocular pressure such as associated with glaucoma, sleep disorders, ulcers, inflammatory disorders and other diseases and disorders associated with the prostaglandin and receptors thereof. The invention further provides methods and pharmaceutical compositions comprising prostaglandin EP4 receptor agonists for the treatment of infertility disorders. More specifically, the present invention relates to such methods and pharmaceutical compositions for inducing ovulation, particularly ovulation triggering.
2. Background
Prostaglandins (PGs) which belong to the prostanoids family are known to have diverse biological activities such as contraction and relaxation of smooth muscle, inhibition and enhancement of neurotransmitter release, inhibition of lipolysis, inhibition of gastric secretion, inhibition of inflammatory mediator release (Coleman et al. Prostanoids and their Receptors. In Comprehensive Medicinal Chemistry, vol. 3, Ed J. C. Emmett, 643-714, Pergamon Press, Oxford, UK, 1990) that are mediated by different receptor subtypes (Coleman et al. Pharmacological Reviews 1994 46 (2), 205-229). Four subtypes of the prostaglandin EP receptor have been identified: EP1, EP2, EP3, and EP4. See also U.S. Pat. Nos. 5,605,814 and 5,759,789.
Knock-out mice lacking each type and sub-type of the EP receptor showed different roles for these receptors (Ushikubi at al. 2000, Jpn. J. Pharmacol. 83, 279-285) in various mechanisms such as ovulation, blood pressure control, closure of ductus arteriosus and bone resorption. Additional roles of EP receptors have been reported such as smooth muscle relaxation in cat trachea for EP2, vasodilatation for EP4 (Gardinier, Br. J. Pharmac. 1986, 87, 45-56; Coleman et al. 1994 Pharmacological Reviews 46 (2), 205-229) and anti-inflammatory activity for EP4 (Takayama et al. 2002, The Journal of Biological Chemistry, 277, 46, 44147-44154). Renal Prostaglandin E2 (PGE2) is crucial of normal renal function by dilating the glomerular microcirculation and vasa recta, supplying the renal medulla and modulating salt and water transport in the distal tubule.
Prostaglandin E2 (PGE2) is a natural ligand for all sub-types of the EP receptor. Consequently, selective effects on one of the sub-types of the EP receptor is impossible to achieve with the endogenous prostaglandins.
Certain prostanoid receptors and modulators of those receptors have been largely reported (Eicosanoids: From Biotechnology to Therapeutic Applications (Plenum Press, New York); Journal of Lipid Mediators and Cell Signalling 14: 83-87 (1996); The British Journal of Pharmacology, 112: 735-740 (1994); WO 96/06822; WO 97/00863; WO 97/00864; WO 96/03380; EP 752421; U.S. Pat. Nos. 6,211,197, 4,211,876; 3,873,566; and Bennett et al. J. Med. Chem., 19(5): 715-717 (1976).
Certain prostaglandin ligands and analogs have been reported to provide biological activity associated with prostaglandins (U.S. Pat. Nos. 6,288,120; 6,211,197; 4,090,019; 4,033,989; 4,003,911). E-type prostaglandin reported to be mediated through interaction with the prostaglandin E receptor(s). Certain compounds also have been reported as EP4 agonists (WO 02/24647, EP 1110949A1, WO03/009872 and WO 03/007941).
It would be desirable to have new compounds and methods for treatment of diseases and disorders associated with the prostaglandin family of compounds.